Insulin resistance and hyperglycemia are characteristic metabolic responses to infections (sepsis) and injury such as surger, burns, trauma and hemorrhage. Recent data suggests that intensive insulin treatment of patients reduces both morbidity and mortality associated with critical illness. However, little is known concerning the role of insulin resistance in the liver and the importance of this resistance in the physiological responses to injury. The liver plays a central role in the development of hyperglycemia and insulin is a primary modulator of hepatic glucose output. Thus, it is important to understand what causes hepatic insulin resistance, and the role this resistance plays in mortality following injury. The few research studies performed to date have focused on changes in insulin signaling in skeletal muscle following different kinds of injury or hemorrhage. Insulin resistance can be explained by changes in the number of insulin receptors or their activity, or a post-receptor defect. Little is known about the cellular mechanisms by which the liver becomes resistant to insulin and the mechanisms and potential reversibility of trauma and hemorrhage-induced insulin resistance in the liver is the subject of this proposal. Preliminary studies suggest that hepatic insulin resistance develops rapidly following surgical trauma and hemorrhage. Proinflammatory cytokines may be involved in the development of this insulin resistance, and there is a defect in at least one insulin regulated signaling pathway. The aims of this proposal are to characterize the effects of experimental trauma (surgery) and hemorrhage on the development of hepatic insulin resistance, to investigate the mechanisms and causative factors leading to the insulin resistance and to determine whether insulin sensitizing agents can reverse or prevent the development of hepatic insulin resistance following trauma and hemorrhage. These studies are important in understanding the role of insulin resistance in the morbidity and mortality following various types of infections, surgery, burns, trauma and hemorrhage.